Is DNA2 c.74+4A>C pathogenic?

DNA2 c.74+4A>C is classified Likely pathogenic in DNA2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-07-22). Very rare (popmax 0.00112%, sas); Associated with Seckel syndrome 8.

What condition is associated with DNA2 c.74+4A>C?

DNA2 c.74+4A>C is associated with Seckel syndrome 8 (ClinVar).

How common is DNA2 c.74+4A>C in the general population?

DNA2 c.74+4A>C is very rare (popmax 0.00112%, sas) (gnomAD).

DNA2 c.74+4A>C

rs2494022602 · VCV2907397

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Conditions

Seckel syndrome 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +4	donor splice region (+4, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.85 · evaluated, not missing
Pangolin	Δ0.59	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.3	GERP 1.5, phastCons 1
Non-coding constraint	Z -1.20	1 kb window · o/e 1.09 · regional · uncalibrated
Overall
CADD	19.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00112% South Asian · 1/89,150 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000346% 5/1,445,442 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00162%	61,688
South Asiangrpmax	0.00112%	89,150
European (non-Finnish)	0.000256%	390,791

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DNA2
Coding: c.74+4A>C
MANE Select: NM_001080449
dbSNP: rs2494022602
Type: single nucleotide variant
Location: chr10:68471787 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.82 · 1 PDB

Full DNA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Seckel syndrome 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNA2 p.Asn306Tyr Uncertain significance ★★ ⚠ same condition
DNA2 p.Ala169= Benign ★★ same condition
DNA2 p.Asn550Ser Benign/Likely benign ★★ same condition
DNA2 p.Leu99= Benign/Likely benign ★★ same condition
DNA2 p.Phe810Leu Benign/Likely benign ★★ same condition
DNA2 p.Pro296= Benign/Likely benign ★★ same condition
DNA2 p.Arg198His Conflicting classifications of pathogenicity ★ ⚠ same condition
DNA2 p.Arg719Ile Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dna2-c-74-plus-4a-c (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown